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Sellar Disorders & Causes of Hyperprolactinemia

Name: Sellar Disorders & Causes of Hyperprolactinemia
Creator: Veli Bakalov, MD

What the sella is made of, what presses on it, and why prolactin climbs

Endocrine·Hypothalamus & Pituitary·4 min read·9 high-yield points·Reviewed by Veli Bakalov, MD @HemeOncBuddy

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The anterior pituitary derives from Rathke pouch (oral ectoderm) and the posterior pituitary from diencephalic neuroectoderm; Rathke remnants form Rathke cleft cysts and craniopharyngiomas.
Craniopharyngioma is a calcified, cystic suprasellar tumor causing bitemporal hemianopia, GH deficiency, diabetes insipidus and hypothalamic obesity.
Suprasellar extension compresses the optic chiasm (bitemporal hemianopia); lateral extension into the cavernous sinus affects CN III, IV, V1, V2 and VI.
Pituitary apoplexy is hemorrhage into an adenoma with thunderclap headache, ophthalmoplegia and shock from acute ACTH deficiency; give hydrocortisone first.
Primary empty sella is usually benign and linked to obesity and idiopathic intracranial hypertension; secondary empty sella follows surgery, radiation or infarction.
Lymphocytic hypophysitis occurs in late pregnancy or postpartum, and ipilimumab (anti-CTLA-4) causes hypophysitis with often permanent ACTH deficiency.
Dopamine from the hypothalamus tonically inhibits prolactin, so stalk compression raises prolactin modestly (usually <100 ng/mL) while other pituitary hormones fall.
Drug causes of hyperprolactinemia: antipsychotics (especially risperidone), metoclopramide, methyldopa, reserpine, verapamil, opioids and estrogen; aripiprazole lowers prolactin.
Hyperprolactinemia from any cause (including primary hypothyroidism via TRH, CKD and pregnancy) suppresses GnRH, causing amenorrhea, infertility, low libido, ED and bone loss.

Development and blood supply

Two origins. The anterior pituitary (adenohypophysis) grows up from Rathke pouch, oral ectoderm from the roof of the primitive mouth, and secretes GH, PRL, ACTH, TSH, FSH and LH. The posterior pituitary (neurohypophysis) grows down from diencephalic neuroectoderm as the infundibulum and releases ADH and oxytocin from axon terminals of supraoptic and paraventricular neurons.

Rathke remnants. Rathke cleft cysts are benign, often incidental, epithelium-lined cysts between the lobes. Craniopharyngioma, the most common sellar-region tumor of childhood, is a calcified, cystic suprasellar mass with cholesterol-rich "machinery-oil" fluid; it causes headache, bitemporal hemianopia, GH deficiency, diabetes insipidus and hypothalamic obesity. The adamantinomatous type (children) carries CTNNB1 (β-catenin) mutations, calcifies and shows wet keratin; the papillary type (adults) carries BRAF V600E and rarely calcifies. Calcification favors craniopharyngioma, because adenomas rarely calcify.

Portal circulation. Superior hypophyseal arteries from the internal carotid feed fenestrated capillaries in the median eminence, where releasing hormones and dopamine enter; long portal veins carry them down the stalk to the anterior lobe's sinusoids. The posterior lobe has a direct arterial supply (inferior hypophyseal arteries). Dependence on low-pressure portal blood explains Sheehan syndrome, infarction of the pregnancy-enlarged gland after postpartum hemorrhage.

Mass effects

Optic chiasm. Upward growth of a macroadenoma (≥1 cm) compresses crossing nasal retinal fibers, producing bitemporal hemianopia. Pressure from below hits inferior nasal fibers first, so superior temporal quadrants go first; craniopharyngiomas pressing from above tend to take the inferior temporal fields first.

Cavernous sinus. CN III, IV, V1 and V2 run in its lateral wall and CN VI beside the internal carotid within it. Lateral extension causes diplopia, ophthalmoplegia, ptosis with a dilated pupil (CN III) and forehead or cheek numbness (V1, V2).

Other effects. Headache, hypopituitarism (GH and gonadotropins are usually lost first) and stalk-effect hyperprolactinemia.

Diabetes insipidus is rare with pituitary adenomas; it points to craniopharyngioma, hypophysitis, metastasis or infiltrative disease such as sarcoidosis or Langerhans cell histiocytosis.

Apoplexy, empty sella and hypophysitis

Pituitary apoplexy. Sudden hemorrhage or infarction of an adenoma, often previously unknown, may follow anticoagulation, surgery, head trauma, pregnancy or starting a dopamine agonist. Thunderclap headache, visual loss, ophthalmoplegia (CN III most often), meningismus and acute ACTH deficiency with hypotension, hyponatremia and shock follow.

Give stress-dose hydrocortisone first, then image and decompress if vision is threatened; thyroid hormone given before cortisol can precipitate adrenal crisis.

Secondary adrenal insufficiency. Aldosterone is spared because the renin-angiotensin system still works, so hyperkalemia and hyperpigmentation are absent, unlike primary adrenal failure, in which ACTH is high.

Acquired sellar disorders

Disorder	Setting	Key features
Pituitary apoplexy	Bleed into an adenoma	Thunderclap headache, ophthalmoplegia, shock
Sheehan syndrome	Postpartum hemorrhage	Infarction; later empty sella
Lymphocytic hypophysitis	Late pregnancy, postpartum	Symmetric enlargement, thick stalk, early ACTH loss
Checkpoint hypophysitis	Ipilimumab (anti-CTLA-4)	Headache, often permanent ACTH deficiency
Primary empty sella	Obese multiparous women, IIH	CSF-filled sella; function usually normal

Empty sella. CSF fills the sella and flattens the gland. The primary form, arachnoid herniation through an incompetent diaphragma sellae, favors obese, multiparous, hypertensive women and idiopathic intracranial hypertension and usually spares function. The secondary form follows surgery, radiation, apoplexy or Sheehan infarction and brings hypopituitarism.

Hypophysitis. Lymphocytic hypophysitis is autoimmune inflammation that causes headache and mimics an adenoma but occurs in late pregnancy or postpartum. Checkpoint inhibitors, most often ipilimumab, cause the same picture.

Causes of hyperprolactinemia

The dopamine brake. Tuberoinfundibular dopamine reaches lactotroph D2 receptors (Gi) through the portal veins and tonically suppresses prolactin; TRH, estrogen, suckling and stress stimulate it. Prolactin is the only anterior hormone mainly under inhibitory control, so stalk interruption (nonfunctioning macroadenoma, craniopharyngioma, trauma) raises prolactin modestly, usually <100 ng/mL, while other anterior hormones fall.

Drugs. D2 antagonists (typical antipsychotics, risperidone and paliperidone, metoclopramide, domperidone, prochlorperazine), dopamine depleters (methyldopa, reserpine), verapamil, opioids and estrogen. Aripiprazole, a partial D2 agonist, lowers prolactin; clozapine and quetiapine rarely raise it.

Physiologic and pathologic causes. Pregnancy (estrogen-driven lactotroph hyperplasia), breastfeeding, nipple or chest-wall stimulation, stress, primary hypothyroidism (TRH stimulates lactotrophs and thyrotroph hyperplasia can mimic an adenoma), CKD (reduced clearance), cirrhosis and recent seizure. Prolactinoma is the most common functioning adenoma; levels >250 ng/mL usually indicate one.

A giant prolactinoma can read only mildly high (hook effect; repeat on diluted serum), and an asymptomatic elevation may be inactive macroprolactin (prolactin–IgG complexes) detected by polyethylene glycol precipitation.

Consequences of hyperprolactinemia

Gonadal shutdown. Prolactin suppresses GnRH pulses through kisspeptin neurons, lowering LH, FSH and sex steroids: oligomenorrhea or amenorrhea, infertility, decreased libido, erectile dysfunction and bone loss. Galactorrhea is a direct effect on estrogen-primed breast tissue. Men and postmenopausal women notice less and present later with macroadenomas and mass effects.